CN103249716A - Electrophilic reagents for monohalomethylation,their preparation and their uses - Google Patents
Electrophilic reagents for monohalomethylation,their preparation and their uses Download PDFInfo
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- CN103249716A CN103249716A CN2011800583974A CN201180058397A CN103249716A CN 103249716 A CN103249716 A CN 103249716A CN 2011800583974 A CN2011800583974 A CN 2011800583974A CN 201180058397 A CN201180058397 A CN 201180058397A CN 103249716 A CN103249716 A CN 103249716A
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- LLSMWLJPWFSMCP-UHFFFAOYSA-N ClCSc1ccccc1 Chemical compound ClCSc1ccccc1 LLSMWLJPWFSMCP-UHFFFAOYSA-N 0.000 description 1
- WDMOTBCSVPXKOZ-UHFFFAOYSA-N FCSC1C=CC=CC1 Chemical compound FCSC1C=CC=CC1 WDMOTBCSVPXKOZ-UHFFFAOYSA-N 0.000 description 1
- TYZNITMSELMDCT-UHFFFAOYSA-N O=S(CF)c1ccccc1 Chemical compound O=S(CF)c1ccccc1 TYZNITMSELMDCT-UHFFFAOYSA-N 0.000 description 1
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- C07C381/12—Sulfonium compounds
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- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
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Abstract
The invention provides electrophilic monohalomethylating reagents, methods for their preparation and methods for preparation of monohalomethylated biologically active compounds using such reagents. Typical monohalomethyl groups transferred are FH2C-, CIH2C- and others. The reagents used for transferal of the groups are described by Formulae A-D : wherein: X = F, CI, Br, I, sulfonate esters, phosphate esters or another leaving group; R11 = tetrafluoroborates, inflates, halogen, perchlorate, sulfates, phosphates or carbonates. The other variables are as defined in the claims.
Description
The invention provides the method for the bioactive compounds of the electric single halogenated methylation reagent of parent, its preparation method and the single halogenated methylation of this reagent preparation of use.
Single methyl fluoride (CH
2F) be very important structure division in the various biological activity organic molecules.Recently occurred two-and the compound of single fluoromethylation as the research of organic biological active compound.Therefore, developed various the containing of multiple structure-CH
2The medicine of F, as: afloqualone, FLUTICASONE PROPIONATE (Jinbo Hu; Wei Zhang; Fei wang; Chem.Commum., 2009,7465-7478), anesthesia Sevoflurane and fluticasone furoate.Single fluoromethylation part is incorporated into effectively and optionally directly uses CH usually in the organic molecule
2FBr carries out or uses such as CH indirectly
2BrI or CH
2The reagent of ClI etc. carries out.These compounds are known as Ha Long or fluorine Lyons (HCFC), and they are subclasses of Chlorofluorocarbons (CFCs) (CFC).
The purposes of this compounds comprises propelling agent and the degreasing solvent (M.Rossberg et al. " Chlorinated Hydrocarbons " in Ullmann ' s Encyclopedia of Industrial Chemistry2006, Wiley-VCH, Weinheim) in refrigeration agent, whipping agent, the medical applications.
Unfortunately, because their high stability, they decompose in lower atmosphere layer unlike many industrial chemicals.In fact they accumulate and finally rise to stratosphere gradually.Uv-radiation in the stratosphere disintegrates CFC, and the chlorine atom or the bromine atoms that discharge damage the ozone layer.Therefore, according to Montreal Protocol, (Pool, R.1989.Replacements for CFCs have proven elusive.Science242:666) progressively eliminated in the manufacturing of this compounds.According to Montreal Protocol, with the consumption and the production that are intended to begin in 2015 to reduce the chemical that consumes ozone.Therefore, need alternative reagent to replace using the reagent of depletion to carry out single fluoromethylation.
Recently, people such as Prakash has reported and has been used for
+CH
2New close electric single fluoromethylation reagent that F directly shifts (the single methyl fluoride of S--S-phenyl-2,3,4,5-tetramethylphenyl sulfonium fluoroform sulphonate and a tetrafluoro borate) (G.K.Surya Prakash; Istvan Ledneczki; Sujith Chacko; George A.Olah; Org.Lett., vol.10, No.4,2008), this reagent is expensive, this mainly is because the cost of substituting group prehnitene.
These reagent (the single methyl fluoride of S--S-phenyl-2,3,4,5-tetramethylphenyl sulfonium a tetrafluoro borate and fluoroform sulphonate) are containing " CH
2F " successfully test in the preparation of bioactive compounds of part, such as among our the common pending application application PT105139 report.
According to the present invention, we have been found that surprisingly now can be with the methyl group-CH of other replacement
2X prepares identical reagent.The particularly important is X wherein and be the reagent of " good leavings group ", described good leavings group is as fluorine, chlorine, bromine, iodine, sulphonate, phosphoric acid ester etc." leavings group " refers to the molecular fragment that leaves with a pair of electronics.We preferably make the leavings group of making good use of, for example, as those skilled in the art clearly be the leavings group of weak base.Good leavings group has low pKa usually.Like this, preferred pKa≤2 or pKa≤0.-1 to-10 or lower pKa normally suitable." good leavings group " for example is conjugate base and the weak base of strong acid.
In organic biological active compound synthetic, these reagent can be used for CH
2The X part is as CH
2F, CH
2Cl, CH
2Br, CH
2I etc. introduce in the organic biological active compound effectively and optionally or introduce in the intermediate.Produce in reaction under the situation of intermediate, end product is by the introducing group-CH of intermediate
2X is converted into the halogenated methyl of expectation and produces.
The present invention is intended to solve Ti Gong Jiang – CH
2X partly introduces the problem of the alternative reagent in the substrate.We find that this can for example realize by the reagent of general formula shown in preparation and the use table 1.
The compound of general formula A, B, C or D is provided according to an aspect of the present invention,
General formula A
Wherein:
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
● R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Be preferably selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate
● get rid of following situation: X=F and R1=R2=R3=R4=R5=H and R6=R7=R8=R9=methyl, R10=H and R11=trifluoromethanesulfonic acid root or tetrafluoroborate; Or
Formula B
Wherein:
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group; And
● R1, R2, R3, R4, R5 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Be preferably selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● and
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate; And
● the naphthalene of R12=resin, naphthalene or replacement
● get rid of following situation: X=F and R1=R2=R3=R4=R5=H and R6=R7=R8=R9=methyl, R10=H and R11=trifluoromethanesulfonic acid root or tetrafluoroborate; And X=F and R1=R2=R3=R4=R5=H and R12=poly-(vinylbenzene-be total to-Vinylstyrene) and R11=trifluoromethanesulfonic acid root or tetrafluoroborate; Or
General formula C
Wherein:
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
● the naphthalene of R13=naphthalene or replacement
● R6, R7, R8, R9, R10 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Be preferably selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate; Or
General formula D
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
● the naphthalene of R13=naphthalene or replacement
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate
● the naphthalene of R12=resin, naphthalene or replacement.
On the other hand, the invention provides for the preparation of containing " CH
2X " the organic biological active compound of part or the method for its intermediate, this method comprises single halogenated methylation step, use therein single halogenated methylation reagent is the compound of general formula A, B, C or D defined herein.
Described single halogenated methylation step for example can comprise the midbody compound that is used in described organic biological active compound with according to single halogenated methylation reagent react of the present invention.The gained compound can be the bioactive compounds of paying close attention to, or further intermediate, and this further intermediate then can be converted to the bioactive compounds of paying close attention to.
On the other hand, the invention provides the method for the preparation of the compound of general formula A, B, C or D, wherein this method comprises the compound for preparing general formula E or F and the step that this compound is changed into the compound of general formula A, B, C or D:
General formula E
Wherein:
● R1, R2, R3, R4, R5 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Be preferably selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
General formula F
Wherein:
● the naphthalene of R12=resin, naphthalene or replacement
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group.
On the other hand, the invention provides as herein defined compound according to the present invention for the preparation of containing " CH
2X " purposes of organic biological active compound of part.
The single halogenated methylation reagent of table 1 –
The single halogenated methylation reagent (continuing) of table 1 –
These reagent can be successfully used to preparation and contain CH
2The organic biological active compound of single halogenated methylation of X part is as FLUTICASONE PROPIONATE, fluticasone furoate, Lotepredenol etabonate (loteprednol etabonate) be used for the intermediate of this compound and other compound of describing as patent US4335121, WO2007/57152, US2002/182185, DE2904614, CH619968.
The invention provides the method for the organic biological active compound of the single halogenated methylation of these reagent preparation of single halogenated methylation reagent, its preparation method and use.
An aspect of of the present present invention relates to single halogenated methylation reagent of general formula described in the table 1 and their preparation.
For example preparation in the one kettle way reaction of of the present invention single halogenated methylation reagent according to table 1 formula of separates each intermediate and maybe will react and the separation of intermediates combination.
Reaction can be begun by the organic compound described in table 2.
Table 2 – starting material
These compounds can be used for the intermediate of preparation table 3.
Table 3-intermediate
Reaction can be carried out in the presence of organic solvent and organic or inorganic catalyzer in suitable temperature range.Reaction can be carried out in the presence of other compound such as oxygenant, reductive agent, organic or inorganic alkali, halogenating agent.This reagent also can be with the form preparation of salt.
The single halogenated methylation reagent that obtains can separate and purifying by any ordinary method.The example of these class methods includes but not limited to: from the reaction mixture direct crystallization; By under controlled pH, adding anti-solvent (anti-solvent); By under controlled pH, adding water; By with organic solvent extraction with immisciblely wash mutually with suitable; By recrystallization in organic solvent or pass through column chromatography.In the treatment step process, also can use resin and gac to be used for purifying list halogenated methylation reagent.
This reagent can use or be used in combination with solid phase as described above.When reagent and resin-bonded, this helps to remove by product from reaction mixture.
Another aspect of the present invention relates to the method with the organic biological active compound of the above-mentioned single halogenated methylation of single halogenated methylation reagent preparation.
The organic biological active compound of this list halogenated methylation can prepare by single halogenated methylation reagent and substrate reactions.For example, substrate can be midbody compound, and it is the precursor compound of the organic-biological compound paid close attention to, comprises direct precursor compound.Such precursor compound will be those skilled in the art institute clearly.
Reaction can be carried out in the presence of organic solvent and organic or inorganic catalyzer in suitable temperature range.Reaction can be carried out in the presence of other compound such as oxygenant, reductive agent, organic or inorganic alkali, halogenating agent.
The organic biological active compound of the single halogenated methylation that obtains can separate and purifying by the method for any routine.The example of these class methods includes but not limited to: from the reaction mixture crystallization; Add anti-solvent to reaction mixture; Under controlled pH, add water.The organic biological active compound also can be by with organic solvent extraction and/or concentrate and to separate, wherein organic layer can be under regulation pH with suitable immiscible solvent wash and can contain reductive agent.After washing or in the washing process, organic layer can be used the siccative drying.In the treatment step process, also can use resin and gac to come the purifying organic extract.Organic biological active compound by isolated single halogenated methylation in the aforesaid reaction can be by the method purifying of any routine, and the example of these class methods includes but not limited to: recrystallization or column chromatography.
The organic biological active compound of resulting single halogenated methylation can be used as the active constituents of medicine of preparation in a known manner, and is used in the treatment of many medical patient's condition.
Provide embodiment hereinafter illustratively, and never should regard it as limitation of the scope of the invention.
Embodiment 1
By the synthetic single methyl fluoride phenyl sulfoxide (compound I I) of the initial one kettle way of methyl phenyl sulfoxide
(65g 463.61mmol) is dissolved in the methylene dichloride (500mL) with methyl phenyl sulfoxide under nitrogen atmosphere.Solution is cooled to the temperature below-5 ℃.Keep identical temperature, slowly add DAST (100mL, 1.65eq).Reaction mixture is warmed to room temperature and under this temperature, stirred 1 hour, under uniform temp, spend the night then.Mixture is cooled to add water after 0 ℃ (300mL) heats reaction mixture then up to 20 ℃-25 ℃ temperature.Stir the gained mixture and separate each layer.Water is extracted with DCM (3x400mL).With the organic phase that merges with saturated NaHCO
3(400mL) and the washing of saturated NaCl solution (400mL), be concentrated into driedly then, obtain the oily resistates.Resistates is cooled to 0 ° of C and be dissolved in methyl alcohol (297.1mL) and the mixture of water (59.4mL) in.((100.5g stirs under uniform temp 1.5eq) and with gained solution and to finish up to reaction N-bromosuccinimide to divide small quantities of NBS of adding.By adding Na
2SO
3Solution (10%, 300mL) and with the mixture cancellation.Add saturated NaHCO
3Solution is 7-8 to regulate pH, then with mixture vacuum concentration under 30 ℃-35 ℃ temperature.Resistates is extracted with methylene dichloride (3x300mL).With the organic phase that merges with anhydrous sodium sulfate drying and then vacuum concentration to obtain crude product be yellow oil, 58g.
Embodiment 2
By the single methyl fluoride phenyl of the initial preparation of aminomethyl phenyl thioether sulfoxide, separate each intermediate
1) preparation chloromethyl phenyl (compound III)
With aminomethyl phenyl thioether (100g, 805.13mmol) dilution in chlorobenzene (602mL).(112.89g 1.05eq), maintains the temperature between 35 ℃-45 ℃ to divide small quantities of adding N-chlorosuccinimide (NCS) under argon atmospher.After 3 hours, filter the suspension that forms and use chlorobenzene (50mL) washing solid.Filtrate water (3x300mL) is washed.The gained organic phase is also concentrated with dried over mgso.Crude product is passed through distillation and purifying, obtain the product of 98g (77%) expectation, be yellow oil (boiling point under the 40Pa: 62 ℃).
2) preparation methyl fluoride phenyl thioether (compound I)
(191.50g 2eq) joins in the mixture of PEG400 (100mL) and acetonitrile (600mL) with cesium fluoride.Mixture is stirred several minutes under argon atmospher, then remove acetonitrile (100mL) by distillation.(100g 630.32mmol) and under 80 ℃-85 ℃ temperature stirs the gained mixture 6 hours to add the chloromethyl phenyl thioether.Filtering mixt and concentrated filtrate.Crude product is passed through distillation and purifying, obtain the product of 52.46g (58.5%) expectation, be light yellow oil (boiling point under the 40Pa: 43 ℃).
3) preparation single methyl fluoride phenyl sulfoxide (compound I I)
(85g 351.63mmol) joins in the mixture of methyl alcohol (250ml) and water (50mL) with methyl fluoride phenyl thioether.The gained mixture is cooled to 0 ℃-5 ℃ temperature.Keep identical temperature range divide small quantities of NBS of adding (75.10g, 1.2eq).Stirred reaction mixture is finished up to reaction, uses Na then
2SO
3Solution (10%, 150mL) with its cancellation.Use NaHCO
3Saturated solution is adjusted to 7-8 with the pH value of reaction mixture.With mixture vacuum concentration under 20 ℃-25 ℃ temperature.With methylene dichloride (200mL, 300mL) extracted residues.The organic layer water (2x300mL) that merges is washed and is concentrated to 1/3 of volume.Add heptane (50mL) and the gained mixture is concentrated again.Crude product by purified by flash chromatography (ethyl acetate/hexane 30:70), is obtained the product of 49.8g (89.6%) expectation, is water white oil under the room temperature, and it is white solid down at-20 ℃.
Embodiment 3
Preparation (3,4-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate
(645mg 4.08mmol) is dissolved in the dry diethyl ether (15ml) with single methyl fluoride phenyl sulfoxide of embodiment 2 under argon atmospher.(0.54ml 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-50 ℃ with ortho-xylene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.68mL, 1.0eq).Stir the mixture and finish up to reaction.Add HBF
4(54%, 1.12mL 2eq) and with gained suspension stirred 30 minutes solution.By filtering separation throw out a tetrafluoro borate, under 0 ℃, wash and drying with diethyl ether.The product that obtains expecting is faint yellow oily solid (1.729g).
1H?NMR(CDCl
3,400MHz):δ7.83(2H,d,J=7.8Hz),7.76-7.56(5H,m),7.43(1H,d,J=8.1Hz),6.54(2H,ddd,J=46.4,J=26.9,J=9.3Hz),2.37(3H,s),2.36(3H,s)。
13C?NMR(CDCl
3,100MHz):δ145.6,141.1,138.8,134.6,132.5,132.2,132.1,131.3,131.07,131.06,129.6,129.06,129.04,90.6(d,J=241.9Hz),20.1,19.9。FT-IR (film): 3018,2956,1448,1259,1162,1058,1029cm
-1
Embodiment 4
Preparation (2,5-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate
(1.01g 6.38mmol) is dissolved in the dry ether (15ml) with single methyl fluoride phenyl sulfoxide of embodiment 2 under argon atmospher.(0.87mL 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-50 ℃ with right-dimethylbenzene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (1.07mL, 1.0eq).Under identical temperature, stir the mixture and finish up to reaction.Add HBF
4At Et
2(54%, 1.76mL 2eq), stirs the gained mixture 30 minutes solution among the O then.By the filtering separation solid, it is fusion at room temperature.In oily mixture, add saturated NaHCO
3Solution (30mL).With gained mixture dichloromethane extraction.With organic phase with dried over mgso and be concentrated into dried.Obtain 1.486g yellow oily solid.
1H?NMR(CDCl
3,400MHz):δ7.80(2H,d,J=7.8Hz),7.77-7.74(1H,m),7.70-7.63(3H,m),7.49(1H,d,J=7.9Hz),7.38(1H,d,J=7.9Hz),6.64(2H,ddd,J=46.8,J=13.0,J=9.5Hz),2.53(3H,s),2.46(3H,s)。
13C?NMR(CDCl
3,100MHz):δ139.8,138.8,136.0,134.6,133.0,131.4,131.2,130.5,130.4,129.0,126.0,89.9(d,J=241.4Hz),21.1,19.5。FT-IR (film): 3018,2958,1494,1448,1259,1160,1060,1029cm
-1
Embodiment 5
By methyl right-the initial preparation of tolyl thioether 1-((methyl fluoride) sulfinyl)-4-methylbenzene, separate each intermediate
1) preparation (chloromethyl) (right-tolyl) sulfane (compound IV)
With methyl right-the tolyl thioether (75g, 542.27mmol) in chlorobenzene (452mL) dilution.(76.07g, 1.05eq), keeping temperature is 35 ℃-45 ℃ to divide small quantities of adding N-chlorosuccinimide (NCS) under argon atmospher.Stirred reaction mixture is finished up to reaction in identical temperature range.Afterwards, solution becomes suspension.Wash with chlorobenzene (50ml) with the suspension filtered of formation and with solid.Filtrate water (3x225mL) is washed.The gained organic phase is also concentrated with dried over mgso.Crude product is passed through distillation and purifying, obtain the product of 102.68g (100%) expectation, be yellow oil (boiling point under the 40Pa: 96 ℃).
2) preparation (methyl fluoride) (right-tolyl) sulfane (compound V)
(149.55g 2eq) joins in the mixture of PEG400 (90mL) and acetonitrile (540mL) with cesium fluoride.Mixture is stirred several minutes under argon atmospher, then remove acetonitrile (90mL) by distillation.Adding (chloromethyl) (right-tolyl) sulfane (102.68g, 492.25mmol).Stirred reaction mixture is finished up to reaction under 80 ℃-85 ℃ temperature.The suspension that filtration forms is also concentrated with filtrate.Crude product is passed through distillation and purifying, obtain the product of 52.09g (68%) expectation, be light yellow oil (boiling point under the 40Pa: 57 ℃).
3) preparation 1-((methyl fluoride) sulfinyl)-4-methylbenzene (compound VI)
(52.09g 320.06mmol) joins in the mixture of methyl alcohol (250mL) and water (50mL) with (methyl fluoride) (right-tolyl) sulfane.The gained mixture is cooled to 0 ℃-5 ℃ temperature.Keep identical temperature range divide small quantities of NBS of adding (68.36g, 1.2eq).Stirred reaction mixture is finished up to reaction under identical temperature range.Afterwards, by adding Na
2SO
3(10%, 150mL) with the reaction mixture cancellation.With saturated NaHCO
3The pH value of solution conditioned reaction mixture is 7-8.With mixture vacuum concentration under 20 ℃-25 ℃ temperature.(200mL 150mL) extracts with methylene dichloride with resistates.The organic layer water (2x300ml) that merges is washed and is concentrated to 1/3 of volume.Add heptane (50mL), remove by distillation then.Crude product by flash chromatography (ethyl acetate/hexane 30:70) purifying, is obtained the product of 48.32g (88%) expectation, be white solid.
Embodiment 6
Preparation (3,4-3,5-dimethylphenyl) (methyl fluoride) (right-tolyl) sulfonium a tetrafluoro borate
(576mg 3.34mmol) is dissolved in the dry ether (15mL) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(0.445mL 1.10eq) joins in the previous solution with ortho-xylene.Mixture is cooled to the temperature below-50 ℃.Temperature-stable after below-50 ℃, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.562mL, 1eq).Stir the mixture and finish up to reaction.Add HBF
4Solution in ether (54%, 0.921mL, 2eq).Gained suspension was stirred 30 minutes.Wash with ether by filtering separation throw out a tetrafluoro borate and under 0 ℃.The product that obtains expecting is oily solid (1.42g).
1H?NMR(CDCl
3,400MHz):δ7.74(2H,d,J=8.4Hz),7.62(1H,s),7.57-7.47(1H,m),7.48(1H,d,J=8.3Hz),7.42(1H,d,J=8.2Hz),6.49(2H,d,J=46.5Hz),2.47(3H,s),2.37(3H,s),2.36(3H,s)。
13C?NMR(CDCl
3,100MHz):δ146.5,145.4,141.0,132.4,132.1,131.6,131.0,128.6,128.5,89.9(d,J=240.2Hz),21.5,19.9,19.6。FT-IR (film): 2985,1592,1492,1450,1295,1228,1066,1025cm
-1
Embodiment 7
Preparation (2,5-3,5-dimethylphenyl) (methyl fluoride) (right-tolyl) sulfonium a tetrafluoro borate
(535mg 3.38mmol) is dissolved in the dry ether (15mL) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(0.42mL 1.0eq) joins in the previous solution with right-dimethylbenzene.Mixture is cooled to the temperature below-50 ℃.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.52mL, 0.92eq).Under identical temperature, stir the mixture and finish up to reaction.Add HBF
4Solution in ether (54%, 1.29mL, 2.77eq).Gained suspension was stirred 30 minutes.Wash with ether by filtering separation throw out a tetrafluoro borate and under 0 ℃.The product that obtains expecting is faint yellow oily solid (2.25g).At room temperature after the heating
1H?NMR(CDCl
3,400MHz):δ7.67(2H,d,J=8.2Hz),7.59(1H,s),7.47(3H,d,J=8.2Hz),7.35(1H,d,J=7.8Hz),6.51(2H,ddd,J=46.0,J=21.4,J=9.4Hz),2.51(3H,s),2.47(3H,s),2.45(3H,s)。
13C?NMR(CDCl
3,100MHz):δ146.5,139.7,138.4,135.9,133.1,132.2,131.1,130.0,128.5,119.8,116.2,89.0(d,J=240.5Hz),21.5,20.9,19.1。FT-IR (film): 1430,1255,1072,1031cm
-1
Embodiment 8
Preparation (methyl fluoride) (isopropyl phenyl) (right-tolyl) sulfonium a tetrafluoro borate
(738mg 4.29mmol) is dissolved in the dry ether (15mL) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(0.66mL 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-50 ℃ with cumene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.72mL, 1eq).Under identical temperature, stir the mixture and finish up to reaction.Add HBF
4Solution in ether (54%, 1.18mL, 2eq).Gained suspension was stirred 30 minutes.Wash with ether by filtering separation throw out a tetrafluoro borate and under 0 ℃.At room temperature the product that obtains expecting after the heating is faint yellow oily solid (2.22g).
1H?NMR(CDCl
3,400MHz):δ7.78-7.74(4H,m),7.54-7.48(4H,m),6.51(2H,d,J=46.5Hz),3.02(1H,m),2.48(3H,s),1.28(6H,d,J=6.8Hz)。
13CNMR(CDCl
3,100MHz):δ146.4,132.1,131.5,131.3,130.3,129.7,124.7,90.8(d,J=240.8Hz),34.2,23.8,23.4,21.6。
FT-IR (film): 1592,1494,1450,1388,1292,1228,1180,1066,1029cm
-1
Embodiment 9
Preparation (tertiary butyl) phenyl) (methyl fluoride) (right-tolyl) sulfonium fluoroform sulphonate
(624mg 3.62mmol) is dissolved in the dry ether (15mL) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(0.561mL 1eq) joins in the previous solution with tert.-butylbenzene.Mixture is cooled to the temperature below-50 ℃.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.61mL, 1eq).Under identical temperature, stir the mixture and finish up to reaction.Wash with ether by filtering separation throw out fluoroform sulphonate and under 0 ℃.At room temperature the product that obtains expecting after the heating is faint yellow oily solid (1.089g), and it is shown as mixture by proton N MR.
Embodiment 10
Preparation (tertiary butyl) phenyl) (methyl fluoride) (right-tolyl) sulfonium a tetrafluoro borate
(495mg 2.87mmol) is dissolved in the dry ether (15mL) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(0.445mL 1eq) joins in the previous solution, then mixture is cooled to the temperature below-50 ℃ with tert.-butylbenzene.Temperature-stable after below-50 ℃, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.483mL, 1eq).Under identical temperature, stir the mixture and finish up to reaction.Add HBF
4Solution in ether (54%, 0.791mL, 2eq), and with gained suspension stirring 30 minutes.Wash with ether by filtering separation throw out a tetrafluoro borate and under 0 ℃.At room temperature obtain the product of 0.5g (wet) expectation after the heating, be faint yellow oily solid.
1H?NMR(CDCl
3,400MHz):δ7.78-7.73(4H,m),7.53-7.50(4H,m),6.38(2H,d,J=46.1Hz),2.51(3H,s),1.32(9H,s)。
13C?NMR(CDCl
3,100MHz):δ147.0,132.4,131.4,131.1,130.9,128.9,125.3,117.8,90.0(d,J=241.3Hz),34.3,31.2,21.5。
FT-IR (film): 1498,1450,1276,1230,1186,1029cm
-1
Embodiment 11
Preparation (methyl fluoride) (naphthalene-2-yl) (right-tolyl) sulfonium a tetrafluoro borate
(481mg 2.79mmol) is dissolved in the dry ether (15mL) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(393.8mg 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-50 ℃ with naphthalene.Temperature-stable after below-50 ℃, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.47mL, 1eq).Under identical temperature, stir the mixture and finish up to reaction.Add HBF
4Solution in ether (54%, 0.77mL, 2eq).Gained suspension was stirred 30 minutes.Wash with ether by filtering separation throw out a tetrafluoro borate and under 0 ℃.At room temperature the product that obtains expecting after the heating is yellow oily solid (1.873g).
1H?NMR(CDCl
3,400MHz):δ8.33(1H,d,J=8.3Hz),8.26(1H,d,J=8.2Hz),8.04-8.01(2H,m),7.82-7.78(3H,m),7.76-7.69(2H,m),7.49(2H,d,J=8.3Hz),6.65(2H,ddd,J=46.8,J=29.7,J=9.5Hz),2.46(3H,s)。
13C?NMR(CDCl
3,100MHz):δ147.0,135.8,134.3,132.3,131.4,131.3,130.6,130.0,129.6,128.3,121.7,116.5,115.8,90.7(d,J=89.6Hz),21.4。FT-IR (film): 1592,1494,1450,1448,1267,1066,1027cm
-1
Embodiment 12
Preparation (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate
(3g 17.42mmol) is dissolved in the dry ether (100ml) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(2.60mL 1.0eq) joins in the previous solution, then mixture is cooled to the temperature below-10 ℃ with prehnitene.Keep identical temperature slowly add Trifluoromethanesulfonic anhydride (2.93mL, 1eq).Under identical temperature, stir the mixture and finish up to reaction.Form peach suspension and after 3 hours, become light gray suspension.By filtering separation throw out fluoroform sulphonate, under 0 ℃ with ether washing and in the temperature vacuum-drying below 30 ℃.Obtain the product of 5.68g (79.44%) expectation, be white solid.
1H?NMR(CDCl
3,400MHz):δ7.68(2H,d,J=8.0Hz),7.47-7.42(3H,m),6.53(2H,ddd,J=46.8,J=22.5,J=9.2Hz),2.48(3H,s),2.45(3H,s),2.37(3H,s),2.29(3H,s),2.28(3H,s)。
13C?NMR(CDCl
3,100MHz):δ146.0,143.7,139.3,138.1,137.0,132.1,130.9,128.2,128.1,122.1,118.9,117.4,116.6,89.8(d,J=240.0Hz),21.6,21.1,17.6,16.88,16.80。FT-IR(KBr):3054,3004,2960,2888,1592,1459,1272,1251,1224,1159,1066,1027。
Embodiment 13
Preparation (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium a tetrafluoro borate
(1.5g 8.71mmol) is dissolved in the dry ether (50ml) with 1-((methyl fluoride) sulfinyl)-4-methylbenzene of embodiment 5 under argon atmospher.(1.3mL 1eq) joins in the previous solution, then mixture is cooled to the temperature below-10 ℃ with prehnitene.Keep identical temperature slowly add Trifluoromethanesulfonic anhydride (1.46mL, 1eq).Under identical temperature, stir the mixture and finish up to reaction.Form peach suspension and after 3 hours, become light gray suspension.Wash with ether by filtering separation throw out fluoroform sulphonate and under 0 ℃.Be dissolved in solid in the methylene dichloride (20ml) and with gained organic solution NaBF
41N solution (6x30ml) washing.With organic phase with dried over mgso and be concentrated into dried.Obtain the product of 1.67g expectation, be white solid.
1H?NMR(CDCl
3,400MHz):δ7.67(2H,d,J=8.2Hz),7.47-7.42(3H,m),6.46(2H,ddd,J=46.7,J=17.2,J=9.4Hz),2.48(3H,s),2.45(3H,s),2.37(3H,s),2.29(3H,s),2.27(3H,s)。
13C?NMR(CDCl
3,100MHz):δ146.0,143.7,139.3,138.1,137.1,132.1,130.9,128.2,128.1,117.4,116.6,89.5(d,J=239.2Hz),21.6,21.1,17.6,16.89,16.82。FT-IR(KBr):3039,2975,2962,1590,1492,1450,1066,1037,1008。
Embodiment 14
Use (2,5-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate in methylene dichloride, to prepare fluticasone 17-propionic ester as reagent
(100mg 0.21mmol) is dissolved in the methylene dichloride (7mL) with the 17-propionic ester carbothioic acid carbothiolic acid of embodiment 4 under argon atmospher.Add cesium carbonate (0.041mg, 0.6eq) and (2,5-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate (131mg, 1.5eq).Water (5mL) cancellation is then spent the night in the reaction mixture stirring.The gained mixture is extracted with methylene dichloride (3x3mL).With the anhydrous MgSO of organic phase that merges
4Dry and concentrated.Resistates by flash chromatography (ethyl acetate/hexane 1:1) purifying and with its crystallization from ethyl acetate and hexane, is obtained the product of 0.085g (79%) expectation, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with FLUTICASONE PROPIONATE.
Embodiment 15
Use (3,4-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate in methylene dichloride, to prepare fluticasone 17-propionic ester as reagent
At room temperature (0.100g 0.21mmol) is dissolved in CH with the 17-propionic ester carbothioic acid carbothiolic acid of embodiment 3
2Cl
2(1.4mL).Add cesium carbonate (0.041g, 0.6eq) and (3,4-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate of embodiment 3 (0.131g, 1.5eq).The reaction mixture stirring is spent the night, and water (5mL) cancellation is also used CH
2Cl
2(3x3mL) extraction.Dry organic phase (the anhydrous MgSO that merges
4) and concentrate.Resistates by flash chromatography (ethyl acetate isohexane 1:1) purifying, then from ethyl acetate and hexane crystallization, is obtained the product of 0.092g (87%) expectation, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with FLUTICASONE PROPIONATE.
Embodiment 16
Use (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate in methylene dichloride, to prepare fluticasone 17-propionic ester as reagent
(0.5g 1.07mmol) is dissolved in the methylene dichloride (7mL) with the 17-propionic ester carbothioic acid carbothiolic acid of embodiment 12.(208.6mg 0.6eq) and at room temperature stirs gained suspension 30 minutes to add cesium carbonate.Adding (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate (700.28mg, 1.5eq).At room temperature stirred reaction mixture is finished up to reaction.Adding heptane (25mL) also stirs gained suspension 15 minutes under uniform temp.By the filtering separation solid and in the temperature vacuum-drying below 35 ℃.Obtain the 1.71g product.With the mixture recrystallization of product by acetone and water.Salt is purified in this recrystallization process.Obtain the product of 0.530g expectation, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with FLUTICASONE PROPIONATE.
Embodiment 17
Use (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium a tetrafluoro borate in methylene dichloride, to prepare fluticasone 17-propionic ester as reagent
(0.5g 1.07mmol) is dissolved in the methylene dichloride (7mL) with the 17-propionic ester carbothioic acid carbothiolic acid of embodiment 13.(208.6mg 0.6eq) and at room temperature stirs gained suspension 30 minutes to add cesium carbonate.Add then (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium a tetrafluoro borate (600.61mg, 1.5eq).At room temperature stirred reaction mixture is finished up to reaction, adds heptane (20mL) then.Gained suspension was stirred 10 minutes.By the filtering separation solid and in the temperature vacuum-drying below 35 ℃.Obtain the 0.85g product afterwards.With the mixture recrystallization of product by acetone and water.Salt is purified in this recrystallization process.Obtain the 0.41g product, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with FLUTICASONE PROPIONATE.
Embodiment 18
Use (2,5-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate in methylene dichloride, to prepare fluticasone 17-furoate as reagent
At room temperature (0.100g 0.20mmol) is suspended in CH with 17-furoate carbothioic acid carbothiolic acid
2Cl
2(1.4mL).Add cesium carbonate (0.039g, 0.55eq) and (2,5-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate of embodiment 4 (0.121g, 1.5eq).The reaction mixture stirring is spent the night, and water (5mL) cancellation is also used CH
2Cl
2(3x3mL) extraction.With the anhydrous MgSO of organic phase that merges
4Dry and concentrated.Resistates by flash chromatography (ethyl acetate/hexane 1:1) purifying and by methylene dichloride and hexane crystallization, is obtained the product of 0.076g (76%) expectation, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with the fluticasone furoate.
Embodiment 19
Use (3,4-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate in methylene dichloride, to prepare fluticasone 17-furoate as reagent
At room temperature (0.100g 0.20mmol) is suspended in CH with 17-furoate carbothioic acid carbothiolic acid
2Cl
2(1.4mL).Add cesium carbonate (0.039g, 0.55eq) and (3,4-3,5-dimethylphenyl) (methyl fluoride) (phenyl) sulfonium a tetrafluoro borate of embodiment 3 (0.121g, 1.5eq).The reaction mixture stirring is spent the night, and water (5mL) cancellation is also used CH
2Cl
2(3x3mL) extraction.With the anhydrous MgSO of organic phase that merges
4Dry and concentrated.Resistates by flash chromatography (ethyl acetate/hexane 1:1) purifying and by methylene dichloride and hexane crystallization, is obtained the product of 0.088g (83%) expectation, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with the fluticasone furoate.
Embodiment 20
Use (methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate in methylene dichloride, to prepare fluticasone 17-furoate as reagent
(0.5g 989mmol) is suspended in the methylene dichloride (7mL) with 17-propionic ester carbothioic acid carbothiolic acid.(193.35mg 0.6eq) and with gained suspension at room temperature stirred 30 minutes to add cesium carbonate.(methyl fluoride) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate of adding embodiment 12 (649.0mg, 1.5eq).At room temperature stirred reaction mixture is finished up to reaction.Adding heptane (mL) also stirs gained suspension 10 minutes under uniform temp.By the filtering separation solid and in the temperature vacuum-drying below 35 ℃.With the mixture recrystallization of product (1.6g) by acetone and water.Salt is purified in this recrystallization process.Obtain the 0.46g product, be white solid.
1H-NMR and
13The C-NMR spectrum is identical with the fluticasone furoate.
Embodiment 21
By the initial preparation monochloro of aminomethyl phenyl thioether methyl phenyl sulfoxide, separate each intermediate
1) by the initial preparation chloromethyl phenyl of aminomethyl phenyl thioether thioether (compound VI I)
With aminomethyl phenyl thioether (100g, 805.13mmol) dilution in chlorobenzene (602mL).Keep temperature be 35 ℃-45 ℃ under argon atmospher, divide small quantities of add N-chlorosuccinimides (NCS) (112.89g, 845.39mmol).After 3 hours, the suspension filtered that forms is also washed with chlorobenzene (50mL).Filtrate water (3X300mL) washing.The gained organic phase is also concentrated with dried over mgso.Crude product is passed through distillation and purifying, obtain the product of 98g (77%) expectation, be yellow oil (boiling point under the 40Pa: 62 ℃).
2) preparation chloromethyl phenyl sulfoxide (compound VIII)
(3g 18.9mmol) is dissolved in the mixture of methyl alcohol (15mL) and water (3mL) with the chloromethyl phenyl thioether.The gained mixture is cooled to 0 ℃-5 ℃ temperature.Keep identical temperature range divide small quantities of NBS of adding (4.04g, 1.2eq).Stirred reaction mixture is finished up to reaction in identical temperature range.Afterwards, by adding Na
2SO
3Solution (10%, 15mL) with the reaction mixture cancellation.With saturated NaHCO
3Solution is adjusted to 7-8 with the pH value of reaction mixture.The gained reaction mixture is extracted with methylene dichloride (3x50mL).With the anhydrous MgSO of organic layer that merges
4Dry and concentrated.Crude product by middle pressure chromatography (ethyl acetate/hexane 2:8) purifying, is obtained the product of 1.381g (42%) expectation, be colourless liquid.
1H?NMR(CDCl
3,400MHz):δ7.71-7.69(2H,m),7.57-7.56(3H,m),4.41(2H,ABQ,J=10.8Hz)。
13C?NMR(CDCl
3,100MHz):δ140.8,132.1,126.3,124.8,61.3。FT-IR(NaCl):3058,3004,2935,1472,1444,1384,1218,1085,1052cm
-1。
Embodiment 22
Preparation (chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate
(12g 68.71mmol) is dissolved in the dry ether (100mL) with the chloromethyl phenyl sulfoxide of embodiment 21 under argon atmospher.(10.3mL 1eq) joins in the previous solution, then mixture is cooled to 5 ℃-0 ℃ temperature with prehnitene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (11.5mL, 1eq).Stir the mixture and finish up to reaction.Wash with ether (50mL) down by the throw out fluoroform sulphonate of filtering separation formation and at 0 ℃.Obtain the product of 16.18g (57.4%) expectation, be white solid.Fusing point: 127 ℃ of 125 –.
1H?NMR(CDCl
3,400MHz):δ7.90(2H,d,J=7.7Hz),7.73-7.66(4H,m),6.99(1H,d,J=11.0Hz),5.94(1H,d,J=11.0Hz),2.51(3H,s),2.42(3H,s),2.29(3H,s),2.28(3H,s)。
13C?NMR(CDCl
3,100MHz):δ144.2,139.1,138.8,137.2,134.8,131.4,130.8,127.5,123.0,116.9,52.4,20.9,17.6,16.9,16.8。FT-IR(KBr):3023,2954,1710,1585,1479,1448,1276,1245,1159,1029cm
-1。
Embodiment 23
Preparation (chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium a tetrafluoro borate
The fluoroform sulphonate (6g) of embodiment 22 is dissolved in the methylene dichloride (30mL).With solution NaBF
4Solution (1M, 5x80mL and 2x50mL) washing.With the gained organic layer with dried over sodium sulfate and be concentrated into dried.Obtain the 4.61g white solid.(yield: 76.8%w/w); Fusing point: 172 ℃ of 171 –.
1H?NMR(CDCl
3,400MHz):δ7.86(2H,d,J=7.5Hz),7.74-7.61(4H,m),5.82(1H,d,J=11.3Hz),5.80(1H,d,J=11.3Hz),2.51(3H,s),2.42(3H,s),2.30(3H,s),2.28(3H,s)。
13C?NMR(CDCl
3,100MHz):δ144.2,139.1,138.9,137.2,134.8,131.5,130.7,127.4,122.8,116.6,52.1,20.9,17.5,16.9,16.8。FT-IR(KBr):3099,3058,2989,1581,1469,1448,1409,1286,1222,1056cm
-1。
Embodiment 24
Preparation (chloromethyl) (3,4-3,5-dimethylphenyl) (phenyl) sulfonium fluoroform sulphonate
(300mg 1.94mmol) is dissolved in the dry ether (7.5mL) with the chloromethyl phenyl sulfoxide of embodiment 21 under argon atmospher.(227mg 1.1eq) joins in the previous solution, and mixture is cooled to the temperature below-60 ℃ with ortho-xylene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.326mL, 1eq).Stir the mixture and finish up to reaction.Wash with ether (50mL) down by filtering separation throw out fluoroform sulphonate and at 0 ℃.Obtain the product of 0.602g (75%) expectation, be the oily solid.
1H?NMR(CDCl
3,400MHz):δ7.93(2H,d,J=7.9Hz),7.74-7.65(5H,m),7.44(1H,d,J=8.1Hz),5.86(2H,s),2.35(6H,s)。
13C?NMR(CDCl
3,100MHz):δ146.0,141.3,135.1,132.0,132.6,131.6,131.4,130.9,128.6,122.5,121.5,118.3,117.7,52.3,20.0,19.7。FT-IR(NaCl):3023,2956,1483,1448,1226,1027cm
-1。
Embodiment 25
Preparation (chloromethyl) (2,5-3,5-dimethylphenyl) (phenyl) sulfonium fluoroform sulphonate
(300mg 1.94mmol) is dissolved in the dry ether (7.5mL) with the chloromethyl phenyl sulfoxide of embodiment 21 under argon atmospher.(227mg 1.1eq) joins in the previous solution, and mixture is cooled to the temperature below-60 ℃ with right-dimethylbenzene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.326mL, 1eq).Stir the mixture and finish up to reaction.Wash with cold ether down by the throw out fluoroform sulphonate of filtering separation formation and at 0 ℃.At room temperature obtain the product of 602mg (75%) expectation after the heating, be the oily solid.
δ7.91(2H,d,J=7.9Hz),7.85(1H,s),7.73-7.64(3H,m),7.44(1H,d,J=7.8Hz),7.33(1H,d,J=7.9Hz),5.97(2H,s),2.52(3H,s),2.44(3H,s)。
13CNMR(CDCl
3,100MHz):δ140.3,138.6,136.1,135.1,132.7,131.5,131.0,129.3,122.2,121.8,120.3,118.7,51.6,20.7,19.3。FT-IR(NaCl):3025,2956,1494,1448,1251,1168,1029cm
-1。
Embodiment 26
Preparation (chloromethyl) (isopropyl phenyl) (phenyl) sulfonium fluoroform sulphonate
(170mg 1.1mmol) is dissolved in the dry ether (5mL) with the chloromethyl phenyl sulfoxide of embodiment 21 under argon atmospher.(145mg 1.1eq) joins in the previous solution, and mixture is cooled to the temperature below-60 ℃ with cumene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.184mL, 1eq).Stir the mixture and finish up to reaction.The orange fluoroform sulphonate of rapid filtering-depositing under-60 ℃ at room temperature obtains the orange viscous oil of 0.399g after the heating, and it is shown as mixture by proton N MR.
Embodiment 27
Preparation (4-(tertiary butyl) phenyl) (chloromethyl) (phenyl) sulfonium fluoroform sulphonate
(200mg 1.29mmol) is dissolved in the dry ether (7.5mL) with the chloromethyl phenyl sulfoxide of embodiment 21 under argon atmospher.(0.191g 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-60 ℃ with tert.-butylbenzene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.217mL, 1eq).Stir the mixture and finish up to reaction.At the orange fluoroform sulphonate of-60 ℃ of following rapid filtering-depositings, at room temperature obtain the viscous oil of 0.487g redness after the heating, it is shown as mixture by proton N MR.
Embodiment 28
Preparation (chloromethyl) (naphthalene-2-yl) (phenyl) sulfonium fluoroform sulphonate
(200mg 1.29mmol) is dissolved in the dry ether (7.5mL) with the chloromethyl phenyl sulfoxide of embodiment 21 under argon atmospher.(0.182g 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-60 ℃ with naphthalene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.217mL, 1eq).Stir the mixture and finish up to reaction.At-60 ℃ after following 4 hours, at-60 ℃ of green fluoroform sulphonates of rapid filtering-depositings down, at room temperature obtain 0.402g (71%) oily solid after the heating.
1H?NMR(CDCl
3,400MHz):δ8.37(1H,d,J=7.6Hz),8.25(2H,dd,J=8.6,2.3Hz),8.01-7.97(4H,m),7.83-7.62(5H,m),6.10(2H,s)。
13C?NMR(CDCl
3,100MHz):δ136.0,135.2,134.3,131.6,131.4,131.1,131.0,130.1,129.7,126.6,121.8,121.6,117.2,52.1。FT-IR(NaCl):3016,2948,1259,1226,1170,1029,912cm
-1。
Embodiment 29
By the initial preparation of methyl p-methylphenyl thioether 1-((chloromethyl) sulfinyl)-4-methylbenzene, separate each intermediate
1) preparation (chloromethyl) (right-tolyl) sulfane (compound I X)
With methyl p-methylphenyl thioether (75g, 542.27mmol) dilution in chlorobenzene (452mL).Under argon atmospher, keep temperature be 35 ℃ of-45 ℃ of branches add in small batches N-chlorosuccinimide (NCS) (76.07g, 1.05eq).Stirred reaction mixture is finished up to reaction in identical temperature range.Afterwards, from solution, isolate solid.Filtering suspension liquid is also used chlorobenzene (50ml) washing solid.Filtrate water (3x225mL) is washed.The gained organic phase is also concentrated with anhydrous magnesium sulfate drying.Crude product by distillation purifying, is obtained the product of 102.68g (100%) expectation, be the oil (boiling point under the 40Pa: 96 ℃) of yellow.
2) preparation 1-((chloromethyl) sulfinyl)-4-methylbenzene (compounds X)
(10g 57.91mmol) joins in the mixture of methyl alcohol (50mL) and water (10mL) with (chloromethyl) (right-tolyl) sulfane.The gained mixture is cooled to 0 ℃-5 ℃ temperature.Keep identical temperature range divide small quantities of NBS of adding (12.37g, 1.2eq).Stirred reaction mixture is finished up to reaction in identical temperature range.Afterwards, by adding Na
2SO
3(10%, 30mL) and with the reaction mixture cancellation.Use saturated NaHCO
3Solution is adjusted to 7-8 with the pH value of reaction mixture.Under 20 ℃-25 ℃ temperature, with the mixture vacuum concentration, use methylene dichloride (40mL, 30mL) extraction then.The organic layer water (2x60ml) that merges is washed and is concentrated into 1/3 of volume.Add heptane (10mL), remove by distillation then.Crude product by flash chromatography (ethyl acetate/hexane 30:70) purifying, is obtained the product of 9.78g (89.51%) expectation, be white solid.
Embodiment 30
Preparation (chloromethyl) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate
(500mg 2.65mmol) is dissolved in the dry ether (5mL) with 1-((chloromethyl) sulfinyl)-4-methylbenzene of embodiment 29 under argon atmospher.(0.40mL 1eq) slowly joins in the previous solution, then mixture is cooled to 5 ℃-0 ℃ temperature with prehnitene.Behind the temperature-stable, keep identical temperature add Trifluoromethanesulfonic anhydride (0.45mL, 1eq).Stir the mixture and finish up to reaction.By filtering to isolate the fluoroform sulphonate of precipitation, and with ether (5mL) 0 ℃ of washing down.Obtain the product of 1.12g (89.74%) expectation, be white solid.Mp=28-30℃。
1H?NMR(CDCl
3,400MHz):δ7.74(2H,d,J=8.2Hz),7.58(1H,s),7.46(2H,d,J=8.1Hz),5.84(2H,ABQ,J=10.9Hz),2.49(3H,s),2.44(3H,s),2.39(3H,s),2.28(3H,s),2.26(3H,s)。
13C?NMR(CDCl
3,100MHz):δ146.5,143.9,139.1,138.6,137.0,132.2,130.7,127.1,52.0,21.6,20.8,17.4,16.8,16.7。FT-IR(KBr):3021,2956,1450,1409,1288,1243,1189,1164,1151,1029cm
-1。
Embodiment 31
Preparation (chloromethyl) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium a tetrafluoro borate
(130mg 0.69mmol) is dissolved in the dry ether (4.5mL) with 1-((chloromethyl) sulfinyl)-4-methylbenzene of embodiment 29.The adding prehnitene (102mg, 1.1eq).Solution is cooled to the temperature below-60 ℃.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.115mL, 0.69mmol).At-60 ℃ after following 4 hours, add HBF
4Solution in ether (54%, 0.168mL, 1.5eq).The gained mixture was stirred 30 minutes.Rapid filtering precipitate a tetrafluoro borate under-60 ℃ obtains 0.242g (89%) white solid.Mp=224℃
1H?NMR(DMSO-d
6,400MHz):δ7.97(2H,d,J=8.4Hz),7.75(1H,s),7.60(2H,d,J=8.2Hz),6.34(2H,ABQ,J=9.8Hz),2.51(3H,s),2.43(3H,s),2.36(3H,s),2.27(3H,s),2.26(3H,s)。
13C?NMR(DMSO-d
6,100MHz):δ145.8,142.9,138.6,137.3,137.0,131.7,130.8,126.6,120.2,119.3,51.2,21.0,20.4,17.2,16.45,16.43。FT-IR(KBr):3043,2967,1496,1446,1407,1288,1247,1220,1195,1076,1049,1031cm
-1。
Embodiment 32
By the initial preparation 2-bromomethylphenyl of aminomethyl phenyl thioether sulfoxide, separate each intermediate
1) preparation methyl phenyl sulfoxide (compounds X I)
(20g 161.03mmol) joins in the mixture of methyl alcohol (100ml) and water (20mL) with the aminomethyl phenyl thioether.Keep 0 ℃-5 ℃ temperature add in batches NBS (34.39g, 1.2eq).Stirring this mixture under identical temperature finishes up to reaction.Afterwards, by adding Na
2SO
3(10%, 60ml) with the reaction mixture cancellation.Use saturated NaHCO
3Solution is adjusted to 7-8 with the pH value of gained reaction mixture.Under 20 ℃-25 ℃ temperature with this mixture vacuum concentration.Resistates is extracted with methylene dichloride (2x125mL).The organic layer water (2x125mL) that merges is washed and is concentrated into 1/3 of volume.Add heptane (20mL), remove by distillation then, obtain the product of 21.64g (95.9%) expectation, be water white oil.
2) preparation 2-bromomethylphenyl sulfoxide (compounds X II)
(21.644g, (27.4mL is 2.2eq) and in the dry acetonitrile (100mL) 154.4mmol) to be dissolved in anhydrous pyridine with methyl phenyl sulfoxide.Under argon atmospher, solution is cooled to-40 ℃.Keep identical temperature slowly to add bromine (49.4g, 2eq) solution in dry acetonitrile (50mL).Mixture was stirred 1 hour down at-40 ℃, at room temperature stir then and spend the night.Under vacuum, steam solvent and resistates is dissolved in the methylene dichloride.With organic layer Na
2S
2O
320% washing is in anhydrous Na
2SO
4Last drying also is concentrated into dried.
(ethyl acetate: purifying hexane 20:80) obtains 16,989g yellow oil (yield 49%) by flash column chromatography with thick material.
Embodiment 33
Preparation (brooethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate
(500mg 2.29mmol) is dissolved in the dry ether (15mL) with the 2-bromomethylphenyl sulfoxide of embodiment 32 under argon atmospher.(339mg 1.09eq) joins in the previous solution, then mixture is cooled to the temperature below-60 ℃ with prehnitene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.385ml, 1.0eq).Stir the mixture and finish up to reaction.The precipitation fluoroform sulphonate that forms by filtering separation, and with ether 0 ℃ of also vacuum-drying of washing down.Obtain the product of 0.779g (70%) expectation, be white solid.Fusing point: 115-116 ℃.
1H?NMR(CDCl
3,400MHz):δ7.93(2H,d,J=7.7Hz),7.71-7.64(4H,m),5.80(1H,d,J=9.9Hz),5.69(1H,d,J=10.0Hz),2.51(3H,s),2.42(3H,s),2.28(3H,s),2.27(3H,s)。
13C?NMR(CDCl
3,100MHz):δ144.1,139.0,138.9,137.0,131.4,130.6,127.1,124.3,118.0,35.2,20.8,17.5,16.9,16.8。FT-IR(KBr):3075,3018,2946,1481,1452,1392,1263,1222,1197,1159,1031cm
-1。
Embodiment 34
Preparation (brooethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium a tetrafluoro borate
(1g 4.58mmol) is dissolved in the dry ether (30mL) with the 2-bromomethylphenyl sulfoxide of embodiment 32 under argon atmospher.(0.678g 1.09eq) joins in the previous solution, then mixture is cooled to the temperature below-60 ℃ with prehnitene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.77mL, 1eq).Stir the mixture and finish up to reaction.At-60 ℃ after following 3 hours, add the solution of HBF4 in ether (54%, 1.11mL, 1.75eq).Gained suspension was stirred 30 minutes.Precipitation a tetrafluoro borate and vacuum-drying by filtering separation formation.Obtain the product of 1.24g (62%) expectation, be white solid.Fusing point: 140-142 ℃.
1H?NMR(CDCl
3,400MHz):δ7.87(2H,d,J=7.5Hz),7.72-7.65(4H,m),5.64(1H,d,J=10.2Hz),5.55(1H,d,J=10.1Hz),2.51(3H,s),2.43(3H,s),2.29(3H,s),2.27(3H,s)。
13C?NMR(CDCl
3,100MHz):δ144.2,139.08,139.02,137.0,134.8,131.5,130.5,126.9,124.1,117.8,34.9,20.8,17.5,16.9,16.8。FT-IR(KBr):3000,2913,2852,2775,1635,1579,1465,1444,1402,1280,1029cm
-1。
Embodiment 35
By the initial preparation of 1-methyl-4-(methyl sulfinyl) benzene 1-((brooethyl) sulfinyl)-4-methylbenzene
(0.814g, (0.939mL is 2.2eq) and in the acetonitrile (21mL) 5.28mmol) to be dissolved in pyridine with 1-methyl-4-(methyl sulfinyl) benzene.Gained solution is cooled to-40 ℃.Keep identical temperature slowly to add bromine (1.7g, 10.56mmol) solution in acetonitrile (10mL).Under-40 ℃, reaction mixture was stirred 1 hour, at room temperature stir then and spend the night.Evaporate solvent and resistates is dissolved in CH
2Cl
2Add Na down (10mL) and at 0 ℃
2S
2O
3The aqueous solution (20%, 10mL).With mixture CH
2Cl
2(3x10mL) extract and the organic phase that merges is washed with HCl10% (15mL), use saturated NaHCO then
3(15mL) washing.With gained organic phase anhydrous Na
2SO
4Dry and concentrated, obtain the product (90%) that 1.109g expects, be white solid.Fusing point: 46-47 ℃.
1H?NMR(CDCl
3,300MHz):δ7.58(2H,d,J=8.2Hz),7.36(2H,d,J=7.9Hz),4.28(2H,ABQ,J=10.0Hz),2.43(3H,s)。
13C?NMR(CDCl
3,100MHz):δ142.8,138.3,130.0,124.8,48.9,21.5。FT-IR(KBr):3027,2939,1594,1492,1353,1176,1105,1041,1016cm
-1。
Embodiment 36
Preparation (brooethyl) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium a tetrafluoro borate
(200mg 0.86mmol) is dissolved in the dry ether (6mL) with 1-((brooethyl) sulfinyl)-4-methylbenzene of embodiment 35 under argon atmospher.(0.127g 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-60 ℃ with prehnitene.Behind the temperature-stable, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.145mL, 1eq).After 30 minutes, add HBF
4Solution in ether (54%, 0.209mL, 1.5eq).Gained suspension was stirred 30 minutes.By filtering separation throw out a tetrafluoro borate and vacuum-drying.Obtain the product of 0.309g (82%) expectation, be white solid.Fusing point: 238 ℃.
1H?NMR(DMSO-d
6,400MHz):δ7.98(2H,d,J=8.4Hz),7.78(1H,s),7.58(2H,d,J=8.2Hz),6.8(2H,ABQ,J=9.08Hz),2.51(3H,s),2.42(3H,s),2.36(3H,s),2.26(3H,s),2.25(3H,s)。
13C?NMR(DMSO-d
6,100MHz):δ145.7,142.8,138.4,137.3,136.8,131.6,130.6,126.2,121.4,120.5,35.0,20.9,20.4,17.1,16.4。FT-IR(KBr):3048,2967,1494,1446,1392,1284,1261,1218,1195,1085,1051,1031,862cm
-1。
Embodiment 37
Preparation (brooethyl) (2,3,4,5-tetramethylphenyl) (right-tolyl) sulfonium fluoroform sulphonate
(200mg 0.86mmol) is dissolved in the dry ether (6mL) with 1-((brooethyl) sulfinyl)-4-methylbenzene of embodiment 35 under argon atmospher.(0.127g 1.1eq) joins in the previous solution, then mixture is cooled to the temperature below-60 ℃ with prehnitene.Temperature-stable after below-60 ℃, keep identical temperature slowly add Trifluoromethanesulfonic anhydride (0.145mL, 1eq).At-60 ℃ after following 4 hours, by filtering separation throw out fluoroform sulphonate and vacuum-drying.Obtain the product of 0.358g (83%) expectation, be white solid.Fusing point: 136-138 ℃.
1H?NMR(CDCl
3,400MHz):δ7.81(2H,d,J=8.4Hz),7.71(1H,s),7.46(2H,d,J=8.2Hz),5.69(2H,ABQ,J=10.0Hz),2.50(3H,s),2.43(3H,s),2.42(3H,s),2.27(3H,s),2.26(3H,s)。
13C?NMR(CDCl
3,100MHz):δ146.5,143.9,138.9,138.8,136.7,132.2,130.6,126.9,120.4,118.5,35.2,21.6,20.8,17.4,16.88,16.81。FT-IR(KBr):3027,2954,1492,1450,1400,1288,1245,1220,1162,1147,1027cm
-1。
Embodiment 38
Use (chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate as reagent by 17-ethoxy carbonyl Oxy-1 1-hydroxyl-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta [a] phenanthrene-initial preparation Lotepredenol etabonate of 17-formic acid (17-ethoxy carbonyl Oxy-1 1-hydroxyl-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta [a] phenanthrene-17-formic acid chloromethyl ester)
With the 17-ethoxy carbonyl Oxy-1 1-hydroxyl-10 of embodiment 22,13-dimethyl-3-oxo-7,8,9,11,12,14,15, (2g 4.78mmol) is suspended in the acetonitrile (20mL) 16-octahydro-6H-cyclopenta [a] phenanthrene-17-formic acid.The adding cesium carbonate (942.08mg, 0.6eq).Gained suspension was stirred 75 minutes down at 35 ℃.(chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate of adding embodiment 22 (2.76g, 1.27eq).The stirring under 35 ℃ of gained suspension is finished up to reaction.Water (50mL) is added in this suspension, then this suspension is cooled to 0 ℃.By filtering separation solid and vacuum-drying under the temperature below 35 ℃ (3.31g).With the mixture (1.86g of solid by acetone and water; 93%w/w) recrystallization.Salt is purified in recrystallization process.
Embodiment 39
Use (chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium a tetrafluoro borate by 17-ethoxy carbonyl Oxy-1 1-hydroxyl-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta [a] phenanthrene-initial preparation Lotepredenol etabonate of 17-formic acid (17-ethoxy carbonyl Oxy-1 1-hydroxyl-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta [a] phenanthrene-17-formic acid chloromethyl ester)
With 17-ethoxy carbonyl Oxy-1 1-hydroxyl-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15, (2g 4.78mmol) is suspended in the acetonitrile (20mL) 16-octahydro-6H-cyclopenta [a] phenanthrene-17-formic acid.The adding cesium carbonate (942.08mg, 0.6eq).Gained suspension was stirred 75 minutes down at 35 ℃.(chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium a tetrafluoro borate of adding embodiment 23 (2.73g, 1.27eq).The stirring under 35 ℃ of gained suspension is finished up to reaction.Water (50mL) is added in the suspension, suspension is cooled to 0 ℃ then.By filtering separation solid and vacuum-drying under the temperature below 35 ℃ (3.70g).With the mixture (2.70g of solid by acetone and water; 135%w/w) recrystallization.Salt is purified in recrystallization process.
Embodiment 40
Use (chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate as reagent preparation (6S, 9R, 16R, 17R)-and 17-(((chloromethyl) sulfenyl) carbonyl)-6,9-two fluoro-11-hydroxyls-10,13,16-trimethylammonium-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-, ten dihydros-3H-cyclopenta [a] phenanthrene-17-base propionic ester
The 17-propionic ester carbothioic acid carbothiolic acid of 2.5g (5.34mmol) is dissolved in the methylene dichloride (25mL).(1.74g 1.0eq) and with the gained mixture at room temperature stirred 30 minutes to add cesium carbonate.(chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate of adding embodiment 22 (3.53g, 1.5eq).Reaction mixture at room temperature stirred up to reaction finish.Mixture is added in the heptane (100mL).Gained suspension was stirred 30 minutes.By the filtering separation solid, with heptane (10mL) washing, and vacuum-drying under the temperature below 35 ℃.With the mixture recrystallization of product by acetone and water.Salt is purified in recrystallization process.Obtain the 2.30g product, be white solid.
Embodiment 41
Use (chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate as reagent preparation (6S, 9R, 10S, 11S, 13S, 16R, 17R)-17-(((chloromethyl) sulfenyl) carbonyl)-6,9-two fluoro-11-hydroxyls-10,13,16-trimethylammonium-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-, ten dihydros-3H-cyclopenta [a] phenanthrene-17-base furans-2-manthanoate
2.5g (4.95mmol) carbothioic acid carbothiolic acid 17-furoate is suspended in the methylene dichloride (25mL).(1.61g 1.0eq) and with the gained mixture at room temperature stirred 30 minutes to add cesium carbonate.(chloromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium fluoroform sulphonate of adding embodiment 22 (3.26g, 1.5eq).Reaction mixture at room temperature stirred up to reaction finish.This mixture is added in the heptane (100mL).Gained suspension was stirred 30 minutes.By the filtering separation solid, with heptane (10mL) washing, and vacuum-drying under the temperature below 35 ℃.With the mixture recrystallization of product by acetone and water.Salt is purified in recrystallization process.Obtain the 2.20g product, be white solid.
Be apparent that to those skilled in the art the present invention is not limited to previous embodiment, can under situation without departing from the spirit and scope of the present invention, implement with other specific form.Therefore, it is illustrative and nonrestrictive that embodiment should regard as, should be with reference to claims, and all fall into the meaning suitable with claims and the variation in the scope all is included in wherein.
Claims (22)
1. the compound of general formula A, B, C or D
General formula A
Wherein:
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
● R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Or be selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino ● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate
● get rid of following situation: X=F and R1=R2=R3=R4=R5=H and R6=R7=R8=R9=methyl, R10=H and R11=trifluoromethanesulfonic acid root or tetrafluoroborate; Or
Formula B
Wherein:
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group; And
● R1, R2, R3, R4, R5 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Or be selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● and
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate; And
● the naphthalene of R12=resin, naphthalene or replacement
● get rid of following situation: X=F and R1=R2=R3=R4=R5=H and R6=R7=R8=R9=methyl, R10=H and R11=trifluoromethanesulfonic acid root or tetrafluoroborate; And X=F and R1=R2=R3=R4=R5=H and R12=poly-(vinylbenzene-be total to-Vinylstyrene) and R11=trifluoromethanesulfonic acid root or tetrafluoroborate; Or
General formula C
Wherein:
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
● the naphthalene of R13=naphthalene or replacement
● R6, R7, R8, R9, R10 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Or be selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate; Or
General formula D
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
● the naphthalene of R13=naphthalene or replacement
● R11=tetrafluoroborate, trifluoromethanesulfonic acid root, halogen, perchlorate, sulfate radical, phosphate radical or carbonate
● the naphthalene of R12=resin, naphthalene or replacement.
2. according to the compound of claim 1, wherein for planting arbitrarily among compd A, B, C or the D, described leavings group is conjugate base or the weak base of strong acid.
3. according to the compound of the general formula A of claim 1, wherein:
● X=F, Cl or Br; And
● R1, R2, R3, R4, R5, R6, R7, R8, R9, R10=H or alkyl or C
1-C
10Alkyl; And
● R11=tetrafluoroborate or trifluoromethanesulfonic acid root.
4. according to the compound of the general formula A of claim 3, wherein:
● R1, R2, R3, R4, R5, R6, R7, R8, R9, R10=H or methyl.
5. according to the compound of the Formula B of claim 1, wherein:
● X=F, Cl or Br; And
● R1, R2, R3, R4, R5=H or alkyl or C
1-C
10Alkyl; And
● R11=a tetrafluoro borate or trifluoromethanesulfonic acid root; And
● R12=resin or naphthalene.
6. according to the compound of the Formula B of claim 5, wherein:
● R1, R2, R3, R4, R5=H or methyl.
7. according to the compound of the general formula C of claim 1, wherein
● X=F, Cl or Br; And
● the R13=naphthalene; And
● R6, R7, R8, R9, R10=H or alkyl or C
1-C
10Alkyl; And
● R11=a tetrafluoro borate or trifluoromethanesulfonic acid root.
8. according to the compound of the general formula C of claim 7, wherein:
● R6, R7, R8, R9, R10=H or methyl.
9. for the preparation of containing " CH
2X " part the organic biological active compound or the method for its intermediate, described method comprises single halogenated methylation step, use therein single halogenated methylation reagent is the compound according to each general formula A, B, C or D among the claim 1-8.
10. according to the method for claim 9, wherein said single halogenated methylation step comprise the midbody compound that is used in described organic biological active compound with according to each single halogenated methylation reagent react among the claim 1-8.
11. according to the method for claim 9 or 10, wherein said single halogenated methylation step comprises organic solvent.
12. the method according to claim 11, wherein said solvent is selected from acetonitrile, heptane, hexane, hexanaphthene, methyl tertiary butyl ether (MTBE), dimethyl formamide (DMF), toluene, 1,2-methylene dichloride, α, α, α-phenylfluoroform, tetrahydrofuran (THF) (THF), methyl-THF, 1,2-glycol dimethyl ether and composition thereof.
13. according to each method among the claim 9-12, wherein said single halogenated methylation step comprises alkali.
14. according to the method for claim 13, wherein said alkali is weak base.
15. according to the method for claim 13 or 14, wherein said alkali is carbonate.
16. according to the method for claim 15, wherein said alkali be selected from cesium carbonate, yellow soda ash and salt of wormwood with and composition thereof.
17. according to the method for claim 16, wherein said alkali is cesium carbonate.
18. for the preparation of the method for the compound of general formula A, B, C or D, wherein said method comprises the compound of preparation general formula E or F and described compound is changed into the step of the compound of general formula A, B, C or D:
General formula E
Wherein:
● R1, R2, R3, R4, R5 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Or be selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group
General formula F
Wherein:
● the naphthalene of R12=resin, naphthalene or replacement
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group.
19. according to the method for claim 10, wherein for compd E or F, described leavings group is conjugate base or the weak base of strong acid.
20. according to each compound among the claim 1-8 for the manufacture of containing " CH
2X " purposes of organic biological active compound of part.
21. according to each method among the claim 9-17, wherein contain " CH
2X " the organic biological active compound be selected from: FLUTICASONE PROPIONATE, fluticasone furoate and Lotepredenol etabonate.
22. the compound of general formula E or F:
General formula E
Wherein:
● R1, R2, R3, R4, R5 are selected from H, alkyl, aryl, alkynyl, thiazolinyl, cycloalkyl, cycloalkenyl group, alkoxyl group, nitro, halogen or amino independently of one another; Or be selected from H, C
1-C
10Alkyl, aryl, C
1-C
10Alkynyl, C
1-C
10Thiazolinyl, C
1-C
10Cycloalkyl, C
1-C
10Cycloalkenyl group, C
1-C
10Alkoxyl group, nitro, halogen or amino
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group;
General formula F
Wherein:
● the naphthalene of R12=resin, naphthalene or replacement
● X=F, Cl, Br, I, sulphonate, phosphoric acid ester or other leavings group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| PT10594211 | 2011-10-18 | ||
| PCT/GB2011/001541 WO2012056201A2 (en) | 2010-10-27 | 2011-10-27 | Electrophilic reagents for monohalomethylation,their preparation and their uses |
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| CN201710130982.XA Division CN106986804A (en) | 2010-10-27 | 2011-10-27 | The electrophilic reagent based on sulfonium cation, its preparation and use for the transfer of monohaloalkyl methyl group |
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| EP (1) | EP2632896B1 (en) |
| CN (2) | CN106986804A (en) |
| ES (1) | ES2626702T3 (en) |
| HU (1) | HUE034570T2 (en) |
| IL (1) | IL225990A (en) |
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| WO (1) | WO2012056201A2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279324A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method |
| CN106279325A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106892952A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106892953A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and its crystal formation and preparation method |
| CN110343142A (en) * | 2018-04-01 | 2019-10-18 | 天津药业研究院有限公司 | A kind of fluoroalkylation method of 17 β of steroidal-thiocarboxylic acid |
| CN110343143A (en) * | 2018-04-01 | 2019-10-18 | 天津药业研究院有限公司 | A kind of preparation method of fluticasone propionate |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT105139B (en) * | 2010-06-01 | 2013-01-29 | Hovione Farmaciencia S A | METHOD FOR THE MONOFLUOROMETHYLATION OF ORGANIC SUBSTRATES FOR THE PREPARATION OF BIOLOGICALLY ACTIVE ORGANIC COMPOUNDS |
| CN106279341A (en) * | 2015-05-11 | 2017-01-04 | 正大天晴药业集团股份有限公司 | A kind of preparation method of fluticasone furoate |
| CN110317238B (en) * | 2018-03-31 | 2022-08-09 | 天津药业研究院股份有限公司 | Preparation method of fluticasone furoate |
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| CN1869039A (en) * | 2005-05-26 | 2006-11-29 | 北京英力科技发展有限公司 | Preparation method of halogenated alkyldiphenyl sulfonium hexafluoro phosphate and application |
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| US4335121A (en) | 1980-02-15 | 1982-06-15 | Glaxo Group Limited | Androstane carbothioates |
| AU2002236495B2 (en) | 2000-11-29 | 2006-05-11 | Allergan, Inc. | Intraocular implants for preventing transplant rejection in the eye |
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| PT105139B (en) | 2010-06-01 | 2013-01-29 | Hovione Farmaciencia S A | METHOD FOR THE MONOFLUOROMETHYLATION OF ORGANIC SUBSTRATES FOR THE PREPARATION OF BIOLOGICALLY ACTIVE ORGANIC COMPOUNDS |
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2011
- 2011-10-27 US US13/882,127 patent/US9290446B2/en not_active Expired - Fee Related
- 2011-10-27 HU HUE11785756A patent/HUE034570T2/en unknown
- 2011-10-27 PT PT117857565T patent/PT2632896T/en unknown
- 2011-10-27 CN CN201710130982.XA patent/CN106986804A/en active Pending
- 2011-10-27 CN CN2011800583974A patent/CN103249716A/en active Pending
- 2011-10-27 EP EP11785756.5A patent/EP2632896B1/en not_active Not-in-force
- 2011-10-27 WO PCT/GB2011/001541 patent/WO2012056201A2/en active Application Filing
- 2011-10-27 ES ES11785756.5T patent/ES2626702T3/en active Active
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2013
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279324A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method |
| CN106279325A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106892952A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106892953A (en) * | 2015-12-21 | 2017-06-27 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and its crystal formation and preparation method |
| CN110343142A (en) * | 2018-04-01 | 2019-10-18 | 天津药业研究院有限公司 | A kind of fluoroalkylation method of 17 β of steroidal-thiocarboxylic acid |
| CN110343143A (en) * | 2018-04-01 | 2019-10-18 | 天津药业研究院有限公司 | A kind of preparation method of fluticasone propionate |
| CN110343142B (en) * | 2018-04-01 | 2022-08-09 | 天津药业研究院股份有限公司 | Fluoroalkylation method of steroid 17 beta-thiocarboxylic acid |
| CN110343143B (en) * | 2018-04-01 | 2022-08-09 | 天津药业研究院股份有限公司 | Preparation method of fluticasone propionate |
Also Published As
| Publication number | Publication date |
|---|---|
| IL225990A (en) | 2015-05-31 |
| US20160130223A1 (en) | 2016-05-12 |
| EP2632896B1 (en) | 2017-03-15 |
| PT2632896T (en) | 2017-06-26 |
| WO2012056201A3 (en) | 2012-09-27 |
| EP2632896A2 (en) | 2013-09-04 |
| HUE034570T2 (en) | 2018-02-28 |
| ES2626702T3 (en) | 2017-07-25 |
| US9290446B2 (en) | 2016-03-22 |
| IL225990A0 (en) | 2013-06-27 |
| US20130274460A1 (en) | 2013-10-17 |
| CN106986804A (en) | 2017-07-28 |
| US9359294B2 (en) | 2016-06-07 |
| WO2012056201A2 (en) | 2012-05-03 |
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